EP0736031A1 - Verbesserungen in beziehung mit chiraler synthese - Google Patents

Verbesserungen in beziehung mit chiraler synthese

Info

Publication number
EP0736031A1
EP0736031A1 EP95904629A EP95904629A EP0736031A1 EP 0736031 A1 EP0736031 A1 EP 0736031A1 EP 95904629 A EP95904629 A EP 95904629A EP 95904629 A EP95904629 A EP 95904629A EP 0736031 A1 EP0736031 A1 EP 0736031A1
Authority
EP
European Patent Office
Prior art keywords
phchch
compounds
compound
cdc1
mmol
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP95904629A
Other languages
English (en)
French (fr)
Other versions
EP0736031B1 (de
Inventor
Stephen Graham Davies
Mario Eugenio Cosamino Polywka
David Roy Fenwick
Frank Reed
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Oxford Asymmetry International PLC
Original Assignee
OXFORD ASYMMETRY Ltd
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Filing date
Publication date
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Publication of EP0736031A1 publication Critical patent/EP0736031A1/de
Application granted granted Critical
Publication of EP0736031B1 publication Critical patent/EP0736031B1/de
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/04—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
    • C07C211/26—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring
    • C07C211/27—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring having amino groups linked to the six-membered aromatic ring by saturated carbon chains
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/04—Formation of amino groups in compounds containing carboxyl groups
    • C07C227/06—Formation of amino groups in compounds containing carboxyl groups by addition or substitution reactions, without increasing the number of carbon atoms in the carbon skeleton of the acid
    • C07C227/08—Formation of amino groups in compounds containing carboxyl groups by addition or substitution reactions, without increasing the number of carbon atoms in the carbon skeleton of the acid by reaction of ammonia or amines with acids containing functional groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
    • C07C229/10—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings
    • C07C229/14—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings to carbon atoms of carbon skeletons containing rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/30—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and unsaturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/32—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing rings other than six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
    • C07D205/085—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams with a nitrogen atom directly attached in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F1/00—Compounds containing elements of Groups 1 or 11 of the Periodic Table
    • C07F1/005—Compounds containing elements of Groups 1 or 11 of the Periodic Table without C-Metal linkages
    • D—TEXTILES; PAPER
    • D02—YARNS; MECHANICAL FINISHING OF YARNS OR ROPES; WARPING OR BEAMING
    • D02G—CRIMPING OR CURLING FIBRES, FILAMENTS, THREADS, OR YARNS; YARNS OR THREADS
    • D02G1/00—Producing crimped or curled fibres, filaments, yarns, or threads, giving them latent characteristics
    • D02G1/02—Producing crimped or curled fibres, filaments, yarns, or threads, giving them latent characteristics by twisting, fixing the twist and backtwisting, i.e. by imparting false twist
    • D02G1/0286—Producing crimped or curled fibres, filaments, yarns, or threads, giving them latent characteristics by twisting, fixing the twist and backtwisting, i.e. by imparting false twist characterised by the use of certain filaments, fibres or yarns

Definitions

  • This invention is concerned with new chiral lithium amides and their use in the synthesis of chiral ⁇ -amino acids, ⁇ -lactams and the like.
  • substantially enantiomerically pure denotes compounds containing at least 80%, advantageously at least 90%, and preferably at least 95% of the desired enantiomer.
  • Carbocyclic aryl groups R may, for example, contain 6-20 carbon atoms, e.g. as in phenyl or naphthyl, and may if desired be substituted, for example by one or more of halo (e.g. chloro, bromo or iodo) , hydroxy, lower (e.g. C ! . 4 ) alkoxy (e.g. methoxy or ethoxy) , lower alkylthio (e.g. methylthio) , lower alkylsulphonyl (e.g. methylsulphonyl), amino, substituted amino (e.g.
  • halo e.g. chloro, bromo or iodo
  • hydroxy e.g. C ! . 4
  • alkoxy e.g. methoxy or ethoxy
  • lower alkylthio e.g. methylthio
  • lower alkylsulphonyl e.g.
  • R groups include phenyl and 3,4- dimethoxyphenyl.
  • the group R 1 can be selected from a wide range of organic groupings, including, for example, aliphatic, cycloaliphatic and araliphatic groups, e.g. containing up to 20 carbon atoms and optionally carrying one or more substituents.
  • R 1 may thus, for example, represent a group selected from C__ 10 alkyl such as methyl or ethyl; C 2 . 10 alkenyl such as vinyl or propenyl; C 3 . 10 cycloalkyl such as cyclopentyl or cyclohexyl; C 3 . 10 cycloalkyl - C ⁇ .. ⁇ alkyl such as cyclopentylmethyl; C 6 . 12 aryl - C___ alkyl such as benzyl; and substituted versions of any of the preceding groups, e.g. carrying substituents as described above for R.
  • R represents optionally substituted phenyl and R 1 represents methyl.
  • R 2 in formula (I) represents an organic group this may, for example, be a lower alkyl group containing 1-10, e.g. 1-6 carbon atoms, as in methyl, ethyl, propyl and butyl groups; a lower (e.g. C 2 - ⁇ 0 ) alkenyl group such as vinyl; a carbocyclic aryl group, e.g. containing 6-20 carbon atoms, such as phenyl or naphthyl; or a heterocyclic group, e.g.
  • compounds (I) according to the invention are a useful source of chiral nucleophiles, capable of undertaking highly stereoselective reactions.
  • they may undergo Michael addition to ⁇ , ⁇ -unsaturated carboxylic acid derivatives such as esters, thioesters, amides, thioamides and oxazolidinones, with high diastereoselectivity, e.g. as represented by the following sequences in the case of addition to an ⁇ , ⁇ -unsaturated ester:
  • R, R 1- and R 2 are as hereinbefore defined;
  • R 3 represents an organic group;
  • R 4 represents an esterifying group such as a lower alkyl or aralkyl group; and
  • R 5 represents a hydrogen atom or an organic group
  • R 3 may, for example, be an organic group as hereinbefore described for R, R 1 or R 2 , and may if desired be substituted, e.g. by one or more functional groups such as protected hydroxyl, amino or carboxaldehyde.
  • the esterifying group R 4 in the starting ⁇ , ⁇ - unsaturated ester is preferably chosen to be relatively bulky, e.g. being a tert-butyl group, in order to minimise competing 1,2-addition of the chiral nucleophile to the carbon atom of the ester carbonyl group.
  • R 5 represents an organic group this may, for example, be as described for any of R, R 1 , R 2 and R 3 .
  • the allylic N-substituent R 2 .CH:CH.CH 2 - in compounds of formulae (Ila) and (lib) may readily and selectively be removed, e.g. under mildly reductive conditions, for example using an agent such as tris(triphenylphosphine) - rhodium(I) chloride in a solvent such as aqueous acetonitrile, and the resulting secondary amine may be subjected to ⁇ -lactam formation, e.g. according to the sequence
  • Cyclisation of a compound (Ilia) or (Illb) to form the desired ⁇ -lactam (IVa) or (IVb) may be effected using any convenient cyclisation agent, for example an appropriate organometallic compound, e.g. a Grignard reagent such as methyl magnesium bromide. Such reactions may conveniently be effected in an aprotic organic solvent, for example an ether such as diethyl ether.
  • N-allyl compounds (Ila) and (lib) prepared as described above may also be cyclised in accordance with the invention, e.g. using methods generally known in the art, for example to generate 5- and 6-membered heterocycles.
  • R, R 1 , R 2 and the asterisk are as hereinbefore defined, e.g. by reaction with a lithium alkyl such as n-butyllithium, for example in a cyclic ether solvent such as tetrahydrofuran at a temperature of less than 0°C, conveniently at about -78 ⁇ C.
  • a lithium alkyl such as n-butyllithium
  • a cyclic ether solvent such as tetrahydrofuran at a temperature of less than 0°C, conveniently at about -78 ⁇ C.
  • the thus-formed compound (I) may advantageously be used in situ without being isolated.
  • R 2 is as hereinbefore defined and X represents a halogen atom such as bromine
  • X represents a halogen atom such as bromine
  • the title compound (8) was obtained by repeating the process of Example 1 using t -butyl cinnamate (7) as the
  • the title compound (14) was obtained by repeating the process of Example 1 using t-butyl 3- (fur-2-yl)propenoate (13) as the Michael acceptor, v, ⁇ (CHCl 3 )/cm _1 1729s
  • Example 2 The procedure of Example 1 was repeated using (S) -N- allyl- ⁇ -methylbenzylamine (2) (0.750g, 4.7 mmol), 1.6M butyllithium (2.52 ml, 4.0 mmol) and t-butyl 4-phenyl-2- butenoate (17) (0.678g, 3.1 mmol) as the Michael acceptor. Flash chromatography on silica gel [ethyl acetate/petroleum ether (1:49)] afforded the title compound (R f 0 .20 ) as a colourless oil ( 0 . 968g, 82%) . ⁇ H (300 MHz ; CDC1 3 ) 7 .40 - 7 .
  • Example 1 The procedure of Example 1 was repeated using (S) -N- allyl- ⁇ -methylbenzylamine (2) (0.840g, 5.22 mmol), 1.6M butyllithium (2.16 ml, 4.17 mmol) and t-butyl 5-phenyl- (E,E) -pentadienoate (19) (0.800g, 3.48 mmol) as the Michael accetor. Flash chromatography on silica gel
  • Example 12 The procedure of Example 12 was repeated using (S) -N- cinnamyl- ⁇ -methylbenzylamine (4) (0.300g, 1.27 mmol), 1.6M butyllithium (0.730 ml, 1.17 mmol), t-butyl cinnamate (7) (0.199g, 0.97 mmol) and (+)- (camphorsulphonyl) -oxaziridine (0.290g, 1.27 mmol).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Mechanical Engineering (AREA)
  • Textile Engineering (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Forging (AREA)
  • Yarns And Mechanical Finishing Of Yarns Or Ropes (AREA)
  • Liquid Crystal Substances (AREA)
EP95904629A 1993-12-24 1994-12-28 Verbesserungen bei chiralen synthesen Expired - Lifetime EP0736031B1 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GB9326403 1993-12-24
GB939326403A GB9326403D0 (en) 1993-12-24 1993-12-24 Improvements in or relating to chiral syntheses
PCT/GB1994/002827 WO1995018134A1 (en) 1993-12-24 1994-12-28 Improvements in or relating to chiral syntheses

Publications (2)

Publication Number Publication Date
EP0736031A1 true EP0736031A1 (de) 1996-10-09
EP0736031B1 EP0736031B1 (de) 2000-05-03

Family

ID=10747180

Family Applications (1)

Application Number Title Priority Date Filing Date
EP95904629A Expired - Lifetime EP0736031B1 (de) 1993-12-24 1994-12-28 Verbesserungen bei chiralen synthesen

Country Status (9)

Country Link
US (1) US6037498A (de)
EP (1) EP0736031B1 (de)
JP (1) JP2964639B2 (de)
AT (1) ATE192449T1 (de)
DE (1) DE69424313T2 (de)
DK (1) DK0736031T3 (de)
ES (1) ES2145260T3 (de)
GB (1) GB9326403D0 (de)
WO (1) WO1995018134A1 (de)

Families Citing this family (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5763569A (en) * 1991-08-23 1998-06-09 The Brigham And Women's Hospital, Inc Calcium receptor-active molecules
US5858684A (en) * 1991-08-23 1999-01-12 The Brigham And Women's Hospital, Inc. Method of screening calcium receptor-active molecules
US6031003A (en) * 1991-08-23 2000-02-29 Nps Pharmaceuticals, Inc. Calcium receptor-active molecules
US6313146B1 (en) 1991-08-23 2001-11-06 Nps Pharmaceuticals, Inc. Calcium receptor-active molecules
US5962314A (en) * 1993-02-23 1999-10-05 Nps Pharmaceuticals, Inc. Calcium receptor-active molecules
EP1275635A1 (de) 1994-10-21 2003-01-15 Nps Pharmaceuticals, Inc. Kalzium-Rezeptor aktive Verbindungen
US6057346A (en) * 1994-12-12 2000-05-02 The United States Of America As Represented By The Department Of Health And Human Services Inhibition of retroviral LTR promoters by calcium response modifiers
ES2326004T3 (es) * 1996-05-01 2009-09-28 Nps Pharmaceuticals, Inc. Compuestos activos de receptor de ion inorganico.
EP1770083B1 (de) * 1996-05-01 2009-04-29 Nps Pharmaceuticals, Inc. Inorganische am Ionen-Rezeptor aktive Verbindungen
EP1258471B1 (de) * 1996-05-01 2007-01-24 Nps Pharmaceuticals, Inc. Verbindungen, die auf anorganische Ionen-Rezeptoren wirken
US7449325B2 (en) 2002-04-08 2008-11-11 Ube Industries, Ltd. Process for enzymatically producing either optically active N-substituted β-amino acids or esters thereof or optically active N-substituted 2-homopipecolic acids or esters thereof

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR960702437A (ko) * 1993-05-06 1996-04-27 로렌스 티. 웰츠 광학활성 3-(1-(알킬아미노))알킬 피롤리딘(optically active 3-(1-alkylamino)alkyl pyrrolidines)

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9518134A1 *

Also Published As

Publication number Publication date
DK0736031T3 (da) 2000-09-04
ATE192449T1 (de) 2000-05-15
JP2964639B2 (ja) 1999-10-18
DE69424313T2 (de) 2000-08-24
ES2145260T3 (es) 2000-07-01
JPH09507221A (ja) 1997-07-22
GB9326403D0 (en) 1994-02-23
US6037498A (en) 2000-03-14
DE69424313D1 (de) 2000-06-08
WO1995018134A1 (en) 1995-07-06
EP0736031B1 (de) 2000-05-03

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